Download ISCEV standard for clinical electro-oculography (2010

Doc Ophthalmol (2011) 122:1–7
DOI 10.1007/s10633-011-9259-0
ISCEV STANDARDS
ISCEV standard for clinical electro-oculography
(2010 update)
Michael F. Marmor • Mitchell G. Brigell •
Daphne L. McCulloch • Carol A. Westall •
Michael Bach • (for the International Society for Clinical Electrophysiology of Vision)
Received: 6 January 2011 / Accepted: 10 January 2011 / Published online: 5 February 2011
Ó Springer-Verlag 2011
Abstract The clinical electro-oculogram (EOG) is
an electrophysiological test of function of the outer
retina and retinal pigment epithelium (RPE) in which
changes in electrical potential across the RPE are
recorded during successive periods of dark and light
adaptation. This document presents the 2010 EOG
Standard from the International Society for Clinical
Electrophysiology of Vision (ISCEV: www.iscev.org).
This revision has been reorganized and updated, but
without changes to the testing protocol from the previous version published in 2006. It describes methods
for recording the EOG in clinical applications and
gives detailed guidance on technical requirements,
practical issues, and reporting of results. It is intended
to promote consistent quality of testing and reporting
within and between clinical centers.
This update was approved by ISCEV, 10 November 2010 at the
Annual General Meeting in Perth, Western Australia. This
document is available on the ISCEV website:
http://www.iscev.org.
Keywords Arden ratio ISCEV standards Clinical electrophysiology Electro-oculogram
(EOG) Light adaptation Retinal pigment
epithelium (RPE)
M. F. Marmor (&)
Eye Institute at Stanford, Stanford University School
of Medicine, Palo Alto, CA, USA
e-mail: [email protected]
M. G. Brigell
Translational Medicine, Novartis Institutes for
Biomedical Research, Cambridge, MA, USA
D. L. McCulloch
Vision Sciences, Glasgow Caledonian University,
Glasgow, UK
C. A. Westall
Ophthalmology and Vision Sciences, University of
Toronto and The Hospital for Sick Children, Toronto,
Canada
M. Bach
Department of Ophthalmology, University Medical
Center Freiburg, Freiburg, Germany
Abbreviations
ERG Electroretinogram
FO
Fast oscillation
RPE Retinal pigment epithelium
This Standard is one of a series of ISCEV Standards and
Guidelines for clinical electrophysiology of vision
[1–8] available for download from www.iscev.org.
This Standard supersedes previous versions of the
ISCEV Standard for Clinical Electro-oculography first
issued in 1993 and most recently revised in 2006 [1, 2].
This current Standard has been reorganized for greater
clarity and to a format consistent with other ISCEV
standards, and it contains updated information without
changes to the 2006 testing protocol.
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Clinical and research users of the EOG are
encouraged to use the current Standard wherever
possible, to achieve consistency of results within and
between test centers. Where a method is used which
deviates from the Standard, the deviations should be
described together with any normative or reference
data.
What is the EOG?
Electrophysiology of the outer retina
in dark and light
There is a difference in electrical potential between
the front and back of the eye, sometimes called the
corneo-fundal potential or standing potential. This
potential is mainly derived from the retinal pigment
epithelium (RPE), and it changes in response to
background levels of retinal illumination. The
potential decreases for 8–10 min after switching to
darkness. Subsequent retinal illumination causes an
initial fall in the standing potential over 60–75 s (the
fast oscillation), followed by a slow but larger rise
over 7–14 min (the light response). These phenomena
arise from ion permeability changes across ion
channels in the basal RPE membrane that are
controlled (at least in part) by the bestrophin gene.
The clinical EOG measures indirectly the amplitude
of the standing potential in the dark and then again at
its maximum amplitude in the light. This is usually
expressed as a ratio of the maximum (peak) amplitude in the light to the minimum (trough) amplitude
in the dark, which is referred to as the light/dark ratio
or Arden ratio. The behavior of the corneo-fundal
potential in the normal eye is predictable in defined
conditions, such as those described in this Standard.
However, changing from prolonged darkness to light
actually initiates a more extended series of changes in
this potential that last for about 2 h in the form of a
damped sinusoidal oscillation.
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of these disorders, there is correlation between effects
on the EOG and on the electroretinogram (ERG),
with the notable exception of disorders of the
bestrophin gene, including Best vitelliform maculopathy, autosomal recessive bestrophinopathy, and
autosomal dominant vitreoretinochoroidopathy (ADVIRC) in which the clinical EOG can be highly
abnormal even in the presence of a normal ERG. The
EOG may also be markedly depressed in acute zonal
occult outer retinopathy (AZOOR).
Principles of clinical EOG measurement
The electrical potential across the RPE causes the
front of the eye to be electrically positive compared
with the back. As a result, potentials measured
between electrodes at each side of an eye will change
as the eye turns horizontally. The EOG method is
widely used to record the eye movements, on the
assumption that the corneo-fundal potential has a
fixed amplitude. In the clinical EOG, we use defined
eye movements to monitor changes in the corneofundal potential. If the test subject looks alternately at
targets separated by a fixed angle, the potential
recorded from electrodes near the canthi will resemble a square wave; the amplitude of this square wave
will be a fixed proportion of the corneo-fundal
potential (see Fig. 1). During a light/dark cycle,
changes in this indirectly measured potential are
directly proportional to the source potentials across
the RPE.
Diseases affecting the light response of the EOG
The light response is affected in diffuse disorders of
the RPE and the photoreceptor layer of the retina
including some characterized by rod dysfunction,
chorio-retinal atrophy, and by inflammation. In most
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Fig. 1 Electrode positions for Standard EOG recording.
a looking left makes left electrodes cornea positive. b looking
right makes right electrodes positive
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The standard method
Amplification and filtering
Technical requirements
Amplifiers should have a band pass between either 0
(d. c.) and 30 Hz or 0.1 and 30 Hz to make
recordings of saccadic eye movements appear as
square waves. For a 30° saccade, the typical EOG
amplitude is between 250 and 1,000 lV with an
essential frequency content of 0–30 Hz. In theory, the
ideal recording technique is d. c. amplification but
this is generally impractical because of base line drift.
Thus, we recommend a.c. recording with a 0.1 Hz
high-pass filter (i.e., a filter that passes only frequencies above 0.1 Hz). If the high pass filter frequency is
higher (e.g., 0.5 Hz), it will distort the square waves,
making identification of overshoot and stepped
saccades very difficult (see Fig. 2). Setting the lowpass filter above 30 Hz serves only to show more
noise in the response (which may affect automatic
cursor placement regimes).
The operator should be able to see the saccadic
recordings as they occur. This monitoring ensures
there are no artifactual signals, no problems such as
Electrodes
These should be relatively nonpolarizable skin electrodes, such as standard medical EEG or ECG
electrodes, of a size appropriate for attachment to
the side of the nose and near the outer canthi. If
baseline drift is excessive, less polarizable electrodes
may be necessary.
Stimulator
The EOG should be performed using a full-field
(Ganzfeld) dome. The Ganzfeld stimulator should
have a comfortable head/chin rest and two red
fixation lights located 15° left and right of center.
The fixation lights should be bright when the light
adapting background is on, and dim (to be just
visible) in the dark.
Idealized record
Light and dark
The dark phase should take place in total darkness,
with the fixation lights dimmed to the minimum
necessary to enable fixation.
The light phase requires even lighting throughout
the dome. This adapting light should appear white
and have a luminance of 100 photopic cd/m2 as
measured with a photometer equipped with a photopic filter. To account for minor variability in
equipment and calibration, a tolerance of ±10%
(0.05 log units) is acceptable within the standard.
Calibration of the Ganzfeld stimulator should be
carried out periodically, e.g., once a year. Modest
room lighting may be turned on during the light phase
as long as ambient luminance is less than that in the
bowl.
Note that adapting light sources of different types,
such as tungsten, halogen, LED, and fluorescent, have
different spectral characteristics and the color may
change with brightness. This makes the definition of
standard lighting inherently imprecise, although for
practical purposes, most ‘‘white’’ light of the correct
luminance will give very similar results. We suggest
that reports indicate the type of light source.
Overshoot
DC recording
AC recording
> 0.5Hz
0
1
> 0.1Hz
2
Time (s)
3
4
0
1
2
3
4
Time (s)
Fig. 2 Idealized saccadic recording with d. c. amplification
(upper) and a. c. amplification (lower). The d. c. records show
ideal square waves (left) and square waves with modest
overshoot (right). The amplitude of the latter should be
measured from the plateaus (red arrows) not the peaks. A. c.
records have less drift, but the square-wave shape of the
responses gets distorted progressively as lower frequencies are
filtered out. Filtering at 0.5–30 Hz (left) distorts square waves
too much for amplitude measurement or for recognition of
overshoot. Filtering at 0.1–30 Hz (right) distorts square waves
only slightly, so that plateaus and amplitudes can still be
accurately recognized and recorded (red arrows)
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amplifier saturation (that can be corrected by adjusting amplifier gain) and that that subjects are compliant with the task.
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without head movement, and the alternation of the
fixation lights should not be anticipated. Practice the
procedure with the recording system to check on the
stability and quality of the recorded saccades.
Preparation of the test subject
Clinical recording
Pupils
Recording of saccades
The pupils should be dilated maximally before testing
and their size recorded. If full pupil dilation is
impossible or undesirable, an attempt should be made
to increase the adapting luminance so that the same
retinal illumination is maintained. The amount of
light passing through the pupil (measured in Trolands) is simply the product of luminance (cd/m2) and
pupil area (mm2). For example, to produce the same
effect upon the retina, twice as much dome luminance
is required with a 5 mm pupil (roughly 20 mm2) than
with a 7 mm pupil (roughly 40 mm2).
The report should describe any deviations from the
Standard.
Electrodes
After suitable skin preparation, place recording
electrodes close to the outer and inner canthi of each
eye as in Fig. 1. Connect the electrodes from each
eye to separate channels of a differential amplifier. A
ground electrode should be placed at an indifferent
point, e.g., on the forehead. The impedance between
any pair of electrodes should not exceed 5 kX. The
electrodes, amplifier, and impedance meter must be
approved for medical use.
Pre-exposure to light
The test subject should be in ordinary room illumination for as long as possible before the test, ideally
upwards of an hour. We advise that examinations such
as indirect ophthalmoscopy and fundus photography
be avoided during this period, but if such examinations have been performed, a recovery time of at least
30 min is required. As near as is practical, the pre-test
light exposure should be the same for all subjects.
Explanations
Explain the procedure fully, noting that the head
position should not change, the eyes should move
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Fixation lights should alternate once per second, for 10 s
out of every minute. The EOG potentials are recorded
only during this period. There should be a warning,
verbal or automatic, of the impending start of each
recording period to ensure readiness of both test subject
and operator. However, there should be no auditory cues
at each alternation of the fixation lights, to avoid
triggering eye movements without actual fixation.
Dark phase
Maintain total darkness for 15 min, except for the
dim fixation lights. EOG recordings should be made
once a minute (for 10 s, as specified in the preceding
paragraph). The operator should have a concurrent
view of the recordings to check for patient compliance and for errors such as noise or overshoot.
Light phase
The dome background light of 100 photopic cd/m2
should be turned on to ‘‘trigger’’ the initial light phase
response and should remain on for the duration of the
light phase. However, if photophobia is severe, it is
recommended that the operator increases the luminance
gradually over a short period (e.g., 20 s). Longer ramps
(e.g., lasting minutes) will alter the responses. Continue
the recording for 10 s out of every minute (as above) for
at least 15 min to register the presence or the absence of a
light peak. Ensure the test subject is seated with the
forehead forward in the headrest of the Ganzfeld dome
for the duration of the test, with eyes open.
Patient compliance
Test subjects will have difficulty performing saccadic
movements if they cannot fixate reliably because of
poor central vision, diplopia, or ocular motility
problems (including nystagmus). Patients with diplopia may be advised to look between the pair of
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images, or one eye can be patched if the suspected
retinal disorder is bilateral. Patients who are very
young or those with learning disabilities may not be
able to perform an EOG. Physical disabilities may
prevent proper positioning.
Even for ‘‘normal’’ subjects, compliance can vary from
fatigue or inattention. Common problems are drifting of
the head back from the dome, irregular eye movements
during the recording, or eye closure during the light phase.
These can be minimized by watching the patient and by
having a real-time view of the EOG recording. Monitoring the patient’s eyes via an infrared camera is useful if
available, but direct observation can suffice during the
light phase. In most cases, gentle coaching and reminders
will remedy difficulty with the task.
Unreliable performance makes the interpretation
of records difficult, but it does not necessarily mean
that useful information cannot be obtained. Just one
or two reliable records near the times of the dark
trough and light peak may be enough to demonstrate
whether there is a light rise or not. This is particularly
important with children, since compliance is often
variable, but by age 7 or 8, many children can
cooperate sufficiently to give valid information.
Analysis and reporting
Saccadic amplitude
Measure the EOG amplitude in lV, either manually
or by a computer algorithm. Overshoot or irregular
(artifactual) saccades should not be measured or
included in calculations (see Fig. 2). The average of
the measurable amplitudes should be calculated
within each 10 s recording period. If a computer
algorithm is used, it is important to ensure that the
values returned represent true EOG amplitudes and
not artifactual records. Particular causes of unreliability are overshoot (see Fig. 2), stepped saccades,
missing saccades, inverse saccades (eye movements
opposite to the direction of the fixation lights), or
eccentric fixation in which the saccade length may
switch between two and more values. When measured manually, these difficulties are fairly obvious.
Dark trough and light peak: smoothing
The average EOG amplitude calculated from each
10 s trial should be plotted. However, there is always
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Fig. 3 Idealized (upper) and realistic (lower) EOG amplitude
versus time curves for a healthy subject. The realistic curve has
noise and variability, but it is not difficult to estimate the
underlying physiologic curve (dashed lines). Arrows show
the dark trough (DT) and light peak (LP), which should reflect
the physiologic curve rather than individual points that might
be higher or lower
‘‘noise’’ in real-life recordings, and the goal of EOG
measurement is to record the physiologic trough and
peak, rather than lowest or highest numerical points
that may represent artifact or noise or occur at an
unlikely point in time (Fig. 3). Thus, the first critical
step is that the underlying physiologic curve be
recognized and drawn to derive a meaningful trough
and peak. This may use a curve-fitting algorithm, a
‘flexicurve’ (curve-fitting ruler) or just a practiced
hand (see Fig. 3), and it relies on knowledge that both
trough and peak are most likely to occur in the
vicinity of 10 min after the change in lighting. It is
helpful if uncertain or artifactual values can be
identified and marked at the time of recording, so that
they can be ignored later when curve fitting.
Standing potentials
This Standard recommends reporting the minimum
standing potential (i.e., the EOG amplitude at the
dark trough). This value is not often used in
diagnosis, but if it is abnormally low, it may indicate
an inactive retina (e.g., total retinal detachment), and
a calculated Arden ratio will be invalid because of the
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small size of the denominator. Normal values for the
minimum standing potential should be established,
but as a guide, standing potentials less than 150 lV
are most likely to produce unreliable Arden ratios.
from the better eye is enhanced at the expense of that
from the weaker eye, which can in fact have a
measured Arden ratio of less than 1.0, solely due to
crosstalk.
Arden ratio calculation
Deviation from standard
The Arden ratio (light/dark ratio) is the ratio between
the light peak and the dark trough of the smoothed
(physiologic) EOG record (Fig. 3).
This Standard represents a basic minimum clinical
procedure. If a laboratory chooses techniques that
vary from the Standard, it is important to cite this
document and specify any deviations, such as a
different luminance level for the adapting light.
Reporting
Clinical reports should state the Arden ratio, the dark
trough amplitude in lV, the time from start of the
light phase to the light peak (if present), the pupil
size, and the type of adapting light source. The report
should also state whether any difficulties were
encountered during the test session which may affect
confidence in the results, such as head movements or
inconsistent saccadic eye movements.
Normative data
No fully authenticated normal reference data are
available at present for the Standard EOG. However,
from a review of existing published data, Arden ratios
\1.5 are generally reported as abnormally low, and
those [2.0 are generally reported as normal; ratios
between 1.5 and 2.0 may be reported as borderline.
Users are strongly urged to establish their own norms
over time.
Interaction between eyes
The EOG potentials from one eye can contaminate the
response from the other. The magnitude of this effect
is approximately 15% with electrodes placed on each
side of the nose close to the inner canthi. This effect
rises to about 40% if the electrodes touch (i.e., act as a
common central electrode on the bridge of the nose).
This crosstalk can give misleading results in cases of
an electrically inactive eye (e.g., total retinal detachment), or absent eye, because the defective eye will
appear to have the same Arden ratio as for the fellow
eye, albeit on a much smaller standing potential. An
even more confusing situation can occur when the
eyes have similar standing potentials but different
Arden ratios. In these cases, the measured Arden ratio
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Additional test: fast oscillation
Some centers also measure the fast oscillation (FO),
in conjunction with the clinical EOG. This response
has the opposite polarity to the EOG. Light onset
causes an initial decrease in the standing potential,
the light trough (LT), that recovers after 30–40 s.
This is caused by a drop in intracellular chloride that
alters ion transport across the basolateral RPE
membrane, resulting in a hyperpolarization. Light
offset causes an initial increase in the standing
potential, the dark rise (DR).
The FO is recorded using the same technical
specifications as the clinical EOG (amplifier, electrode
placement, fixation targets, background luminance,
and 1 per second saccades). To record the FO,
saccades and the recording is continuous without
interruption for the duration of the test. The FO test
protocol consists of light (100 cd/m2) and dark periods
alternated every 60 s to induce the FOs, which have a
near sinusoidal appearance. During each light interval,
a light trough (LT) develops and begins to rise again
after 30–40 s. The subsequent interval of darkness
results in a dark rise (DR) at 30–40 s following the
onset of darkness. The total number of light–dark
intervals should be at least 4, making a total test time
of 8 min. Pre-adaptation does not affect the FO, and so
this test can be performed either independently or in
conjunction with the clinical EOG.
Figure 4 shows an idealized representation of the
FO cycles. The ratio of DP to LT of the FO should be
reported. The normal DP/LT amplitude ratio is
typically between 1.05 and 1.30. It should be noted
that high blood glucose levels increase the FO
amplitudes.
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Standing Potential
(µV/deg)
Fast Oscillations
DR
LT
Time (minutes)
Fig. 4 Idealized representation of fast oscillations (FO). In the
dark intervals (black bars), the standing potential increases to a
dark rise maximum (DR). Following light onset, the standing
potential falls to a light trough (LT). The FO ratio of the DR:
LT standing potentials should be recorded
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clinical electro-oculography. Doc Ophthalmol 85:115–124
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(2003) Guidelines for calibration of stimulus and recording
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